Role of Sensory Nerves in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis results from the deposition and proliferation of extracellular matrix components in the lungs. Despite being an airway disorder, pulmonary fibrosis also has notable effects on the pulmonary vasculature, with the development and severity of pulmonary hypertension tied closely to patient mortality. Furthermore, the anatomical proximity of blood vessels, the alveolar epithelium, lymphatic tissue, and airway spaces highlights the need to identify shared pathogenic mechanisms and pleiotropic signaling across various cell types. Sensory nerves and their transmitters have a variety of effects on the various cell types within the lungs; however, their effects on many cell types and functions during pulmonary fibrosis have not yet been investigated. This review highlights the importance of gaining a new understanding of sensory nerve function in the context of pulmonary fibrosis as a potential tool to limit airway and vascular dysfunction.

Keywords: calcitonin gene-related peptide; cough; edema sleep apnea; pericytes; pulmonary fibrosis; pulmonary hypertension; sensory nerves; substance P.

Figure 1

Perivascular sensory nerves on mouse pulmonary arteries. Representative calcitonin gene-related peptide (CGRP) staining (maximum z projections) on the surface of a ~100 µm pulmonary artery. Dotted lines indicate approximate vessel edge. Scale bar = 50 µm.

Figure 2

Summary of sensory nerve signaling in airways during pulmonary fibrosis (PF). Calcitonin gene-related peptide (CGRP) and substance P (SP) promote bronchoconstriction, airway proliferation, and chronic cough. Whereas CGRP limits the formation of fibrotic foci by attenuating fibroblast and macrophage activation, SP diminishes fibroblast signaling and potentiates macrophage inflammation. Image created with Biorender.

Figure 3

Summary of sensory nerve signaling in blood vessels during pulmonary fibrosis. Calcitonin gene-related peptide (CGRP) signaling promotes vasoconstriction and attenuates vascular remodeling in pulmonary hypertension (PH). In contrast, substance P (SP) can elicit vasoconstriction or dilation and can promote the proliferation of SMCs, leading to vascular remodeling. Whereas CGRP acts on both SMCs and ECs, SP acts solely on ECs. Image created with Biorender.

Figure 4

Summary of pericyte signaling during pulmonary fibrosis (PF). Inflammatory signaling leads to the transition of pericytes into myofibroblasts, which contribute to the formation of fibrotic foci and vascular remodeling in PF. Image created with Biorender.